Match!

Tumor Mutational Burden as an Independent Predictor of Response to Immunotherapy in Diverse Cancers

Published on Nov 1, 2017in Molecular Cancer Therapeutics4.856
· DOI :10.1158/1535-7163.MCT-17-0386
Aaron M. Goodman10
Estimated H-index: 10
(UCSD: University of California, San Diego),
Shumei Kato18
Estimated H-index: 18
(UCSD: University of California, San Diego)
+ 6 AuthorsRazelle Kurzrock101
Estimated H-index: 101
(UCSD: University of California, San Diego)
Sources
Abstract
Immunotherapy induces durable responses in a subset of patients with cancer. High TMB may be a response biomarker for PD-1/PD-L1 blockade in tumors such as melanoma and non-small cell lung cancer (NSCLC). Our aim was to examine the relationship between TMB and outcome in diverse cancers treated with various immunotherapies. We reviewed data on 1,638 patients who had undergone comprehensive genomic profiling and had TMB assessment. Immunotherapy-treated patients (N = 151) were analyzed for response rate (RR), progression-free and overall survival (PFS, OS). Higher TMB was independently associated with better outcome parameters (multivariable analysis). The RR for patients with high (≥ 20 mutations/mb) vs. low to intermediate TMB was 22/38 (58%) vs. 23/113 (20%) (P = 0.0001); median PFS, 12.8 vs. 3.3 months (P =
Figures & Tables
  • References (51)
  • Citations (302)
📖 Papers frequently viewed together
2,853 Citations
1,656 Citations
201541.06Science
24 Authors (Naiyer A. Rizvi, ..., Timothy A. Chan)
2,683 Citations
78% of Scinapse members use related papers. After signing in, all features are FREE.
References51
Newest
#1Zachary R. Chalmers (Foundation Medicine)H-Index: 15
#2Caitlin F. Connelly (Foundation Medicine)H-Index: 11
Last. Garrett M. Frampton (Foundation Medicine)H-Index: 42
view all 23 authors...
370 CitationsSource
Immune-checkpoint inhibitors are revolutionizing the treatment of many types of solid cancer. Expression of the inhibitory immune-checkpoint proteins programmed cell-death 1 (PD-1) and its ligands (PD-L1 and PD-L2) are frequently detected in haematological malignancies, and agents targeting these proteins have activity in such diseases, notably Hodgkin lymphoma. Herein, the current evidence supporting the roles of PD-1–PD-L1 blockade in the treatment of various B-cell malignancies is reviewed.
107 CitationsSource
#1Amélie Boichard (UCSD: University of California, San Diego)H-Index: 5
#2Igor Tsigelny (UCSD: University of California, San Diego)H-Index: 34
Last. Razelle Kurzrock (UCSD: University of California, San Diego)H-Index: 101
view all 3 authors...
ABSTRACTImmunotherapy with checkpoint inhibitors, such as antibodies blocking the programmed cell-death receptor-1 (PD-1), has resulted in remarkable responses in patients having traditionally refractory cancers. Although response to PD-1 inhibitors correlates with PD-1 ligand (PD-L1 or PD-L2) expression, PD-1 ligand positivity represents only a part of the predictive model necessary for selecting patients predisposed to respond to immunotherapy. We used all genomic, transcriptomic, proteomic an...
25 CitationsSource
#1Yulian Khagi (UCSD: University of California, San Diego)H-Index: 4
#2Razelle Kurzrock (UCSD: University of California, San Diego)H-Index: 101
Last. Sandip Pravin Patel (UCSD: University of California, San Diego)H-Index: 18
view all 3 authors...
With the advent of targeted therapies, there has been a revolution in the treatment of cancer across multiple histologies. Immune checkpoint blockade has made it possible to take advantage of receptor-ligand interactions between immune and tumor cells in a wide spectrum of malignancies. Toxicity in healthy tissue, however, can limit our use of these agents. Immune checkpoint blockade has been approved in advanced melanoma, renal cell cancer, non-small cell lung cancer, relapsed refractory Hodgki...
32 CitationsSource
#1Willy HugoH-Index: 20
#2Jesse M. ZaretskyH-Index: 14
Last. Roger S. LoH-Index: 45
view all 18 authors...
51 CitationsSource
#1Wenqiang Ma (UMN: University of Minnesota)H-Index: 2
#2Shihua Li (CAS: Chinese Academy of Sciences)H-Index: 14
Last. GeorgeFGaoH-Index: 79
view all 19 authors...
Summary Zika virus (ZIKV) persists in the semen of male patients, a first for flavivirus infection. Here, we demonstrate that ZIKV can induce inflammation in the testis and epididymidis, but not in the prostate or seminal vesicle, and can lead to damaged testes after 60 days post-infection in mice. ZIKV induces innate immune responses in Leydig, Sertoli, and epididymal epithelial cells, resulting in the production of pro-inflammatory cytokines/chemokines. However, ZIKV does not induce a rapid an...
178 CitationsSource
#1Douglas B. Johnson (VUMC: Vanderbilt University Medical Center)H-Index: 47
#2Garrett M. Frampton (Foundation Medicine)H-Index: 42
Last. Christine M. Lovly (VUMC: Vanderbilt University Medical Center)H-Index: 37
view all 27 authors...
Therapeutic antibodies blocking programmed death-1 and its ligand (PD-1/PD-L1) induce durable responses in a substantial fraction of melanoma patients. We sought to determine whether the number and/or type of mutations identified using a next generation sequencing (NGS) panel available in the clinic were correlated with response to anti-PD-1 in melanoma. Using archival melanoma samples from anti-PD-1/PD-L1-treated patients, we performed hybrid capture-based NGS on 236-315 genes and T-cell recept...
117 CitationsSource
#1Sadakatsu Ikeda (UCSD: University of California, San Diego)H-Index: 10
#2Aaron M. Goodman (UCSD: University of California, San Diego)H-Index: 10
Last. Razelle Kurzrock (UCSD: University of California, San Diego)H-Index: 101
view all 9 authors...
Metastatic basal cell carcinomas are rare malignancies harbouring Hedgehog pathway alterations targetable by SMO antagonists (vismodegib/sonidegib). We describe, for the first time, the molecular genetics and response of a patient with Hedgehog inhibitor-resistant metastatic basal cell carcinoma who achieved rapid tumour regression (ongoing near complete remission at 4 months) with nivolumab (anti-PD1 antibody). He had multiple hallmarks of anti-PD1 responsiveness including high mutational burde...
31 CitationsSource
#1Marcin KowanetzH-Index: 32
#2Wei ZouH-Index: 1
Last. Matthew D. HellmannH-Index: 50
view all 19 authors...
14 CitationsSource
#1Claud Grigg (CUMC: Columbia University Medical Center)H-Index: 5
#2Naiyer A. Rizvi (CUMC: Columbia University Medical Center)H-Index: 59
Research in cancer immunology is currently accelerating following a series of cancer immunotherapy breakthroughs during the last 5 years. Various monoclonal antibodies which block the interaction between checkpoint molecules PD-1 on immune cells and PD-L1 on cancer cells have been used to successfully treat non-small cell lung cancer (NSCLC), including some durable responses lasting years. Two drugs, nivolumab and pembrolizumab, are now FDA approved for use in certain patients who have failed or...
90 CitationsSource
Cited By302
Newest
#1Antonio Travaglino (University of Naples Federico II)H-Index: 16
#2Antonio Raffone (University of Naples Federico II)H-Index: 16
Last. Fulvio Zullo (University of Naples Federico II)H-Index: 45
view all 7 authors...
We aimed to classify undifferentiated/dedifferentiated carcinoma (UDC/DDC) according to the four TCGA molecular subgroups of endometrial cancer: microsatellite-instable/hypermutated (MSI), POLE-mutant/ultramutated (POLE), copy-number-low/p53-wild-type (p53wt), and copy-number-high/p53-abnormal (p53abn), through a systematic review and meta-analysis. Electronic databases were searched from January 2013 to July 2019 for studies assessing the TCGA classification in endometrial UDC/DDC series. Poole...
3 CitationsSource
#1Kate D. Sutherland (University of Melbourne)H-Index: 18
#2Joseph H.A. Vissers (University of Melbourne)H-Index: 9
Source
#1Valentina BianchiH-Index: 5
#2Alexandre HarariH-Index: 36
Last. George CoukosH-Index: 72
view all 3 authors...
Source
#1Mina Nikanjam (UCSD: University of California, San Diego)H-Index: 10
#2Paul Riviere (UCSD: University of California, San Diego)H-Index: 2
Last. Razelle Kurzrock (UCSD: University of California, San Diego)H-Index: 101
view all 6 authors...
High tumor mutational burden (TMB) predicts checkpoint blockade responsiveness, although the association with outcomes may be nuanced in certain tissue contexts. The correlation between TMB and cyt...
Source
#1Zhening Zhang (PKU: Peking University)H-Index: 1
#2Siyuan Cheng (PKU: Peking University)
Last. Zhi Peng (PKU: Peking University)H-Index: 8
view all 9 authors...
Abstract Introduction Immune checkpoint inhibitors (ICIs) have been approved for the late-line treatment of unresectable gastrointestinal tumors, but their efficacy and safety in the neoadjuvant setting have not been described. Whether dMMR/MSI-H populations benefit from preoperative ICIs plus surgery remains undefined. Materials and methods Six consecutive patients managed at our institution received neoadjuvant ICIs and surgery for advanced, resectable, and MSI-H gastrointestinal tumors. All p...
Source
BRAF-V600 mutations occur in approximately 50% of patients with metastatic melanoma. Immune-checkpoint inhibitors and targeted therapies are both active as first-line treatments in these patients r...
Source
#1Juan L. TrincadoH-Index: 5
#2Marina Reixachs-Solé (ANU: Australian National University)H-Index: 1
Last. Eduardo Eyras (ANU: Australian National University)H-Index: 44
view all 5 authors...
Immunotherapies provide effective treatments for previously untreatable tumors, but the molecular determinants of response remain to be elucidated. Here, we describe a pipeline, ISOTOPE (ISOform-guided prediction of epiTOPEs In Cancer), for the comprehensive identification of cancer-specific splicing-derived epitopes. Using RNA sequencing and mass spectrometry for MHC-I associated proteins, ISOTOPE identified neoepitopes from cancer-specific splicing event types that are potentially presented by...
Source
#1Jacob Friedman (Rush University Medical Center)
#2Jane K. Schumacher (Rush University Medical Center)
Last. Pete S. Batra (Rush University Medical Center)H-Index: 35
view all 6 authors...
BACKGROUND Olfactory neuroblastoma (ONB) is a rare skull-base malignancy associated with delayed local recurrence. Treatment options in recurrent disease are few and unreliable. We undertook analysis of the ONB exome and immune environment in order to identify potential future immunotherapy treatment options. METHODS Retrospective chart review and next-generation targeted 595-gene genomic profiling was performed on a cohort of 14 ONB cases utilizing Tempus proprietary DNA and RNA sequencing tech...
Source
#1Jiawei Li (PKU: Peking University)
#2Haiqing Chen (Fudan University)
Last. Fan Yang (PKU: Peking University)H-Index: 29
view all 5 authors...
BACKGROUND Nonsynonymous tumor mutation burden (NSTMB) could affect the prognosis of esophageal cancer (EC) patients, but differentially expressed genes between EC patients with different NSTMB have not been explored. Our study aimed to compare differentially expressed genes between EC patients with different NSTMB (high vs. low). METHODS RNA-seq data for EC patients were downloaded from The Cancer Genome Atlas (TCGA). The edgeR package was used to identify differentially expressed genes between...
Source
#1Zhenyu Yang (Sichuan University)H-Index: 2
#2Shiyou Wei (Sichuan University)H-Index: 2
Last. Lunxu Liu (Sichuan University)H-Index: 37
view all 5 authors...
BACKGROUND Biomarkers for stratifying patients that could benefit from immune checkpoint inhibitors are necessary. Tumour mutation burden has recently become a promising biomarker in cancer, but the associations between tumour mutation burden and outcomes of immune checkpoint inhibitors treatment were not well-documented in present studies. METHODS We searched PubMed, Web of Science and EMBASE databases up to 1 October 2019. Studies evaluated the association between tumour mutation burden and cl...
Source